Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom.
Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom.
Genes Dev. 2024 Aug 20;38(13-14):631-654. doi: 10.1101/gad.351701.124.
Selfish DNA modules like transposable elements (TEs) are particularly active in the germline, the lineage that passes genetic information across generations. New TE insertions can disrupt genes and impair the functionality and viability of germ cells. However, we found that in - hybrid dysgenesis in , a sterility syndrome triggered by the -element DNA transposon, germ cells harbor unexpectedly few new TE insertions despite accumulating DNA double-strand breaks (DSBs) and inducing cell cycle arrest. Using an engineered CRISPR-Cas9 system, we show that generating DSBs at silenced -elements or other noncoding sequences is sufficient to induce germ cell loss independently of gene disruption. Indeed, we demonstrate that both developing and adult mitotic germ cells are sensitive to DSBs in a dosage-dependent manner. Following the mitotic-to-meiotic transition, however, germ cells become more tolerant to DSBs, completing oogenesis regardless of the accumulated genome damage. Our findings establish DNA damage tolerance thresholds as crucial safeguards of genome integrity during germline development.
自私的 DNA 模块，如转座元件 (TEs)，在生殖细胞中特别活跃，生殖细胞是将遗传信息代代相传的谱系。新的 TE 插入会破坏基因，并损害生殖细胞的功能和存活能力。然而，我们发现，在 - 杂种不育症中，一种由 - 元件 DNA 转座子引发的不育综合征，尽管积累了 DNA 双链断裂 (DSBs) 并诱导细胞周期停滞，但生殖细胞中出乎意料地只有很少的新 TE 插入。利用工程化的 CRISPR-Cas9 系统，我们表明，在沉默的 - 元件或其他非编码序列处产生 DSBs 足以独立于基因破坏诱导生殖细胞丢失。事实上，我们证明，发育中的和成年的有丝分裂生殖细胞对 DSBs 的敏感性呈剂量依赖性。然而，在有丝分裂到减数分裂的转变之后，生殖细胞对 DSBs 的耐受性更强，无论积累的基因组损伤如何，都能完成卵子发生。我们的发现确立了 DNA 损伤耐受阈值作为生殖细胞发育过程中基因组完整性的重要保护机制。
